REVIEWARTICLE

A systematic literature review of the efficacy, effectiveness,and safety of filgrastim

David C. Dale1 & Jeffrey Crawford2& Zandra Klippel3 & Maureen Reiner4 &

Timothy Osslund5& Ellen Fan6

& Phuong Khanh Morrow3& Kim Allcott7 &

Gary H. Lyman1,8

Received: 8 March 2017 /Accepted: 15 August 2017 /Published online: 22 September 2017# The Author(s) 2017. This article is an open access publication

AbstractPurpose Filgrastim (NEUPOGEN®) is the originator recombi-nant human granulocyte colony-stimulating factor widely usedfor preventing neutropenia-related infections and mobilizing he-matopoietic stem cells. This report presents findings of a system-atic literature review and meta-analysis of efficacy and safety oforiginator filgrastim to update previous reports.Methods A literature search of electronic databases, congressabstracts, and bibliographies of recent reviews was conductedto identify English-language reports of clinical trials and

observational studies evaluating filgrastim in its US-approvedindications up to February 2015. Two independent reviewersassessed titles/abstracts and full texts of publications, and extract-ed data from studies that compared originator filgrastim vs pla-cebo or no treatment. For outcomeswith sufficient homogeneousdata reported across studies, meta-analysis was performed andrelative risk (RR) determined. Data were summarized descrip-tively for all other evaluated outcomes.Results A total of 1194 unique articles evaluating originatorfilgrastim were identified, with 25 meeting eligibilitycriteria for data extraction: 18 randomized controlled tri-als, 2 nonrandomized clinical trials, and 5 observational stud-ies. In chemotherapy-induced neutropenia (CIN), filgrastim vsplacebo or no treatment significantly reduced febrile neutro-penia incidence (RR 0.63, 95% CI 0.53–0.75) and grade 3 or 4neutropenia incidence (RR 0.50, 95% CI 0.37–0.68). The mostcommonly reported adverse event (AE) with filgrastim wasbone pain (RR 2.61, 95% CI 1.29–5.27 in CIN). Additionalefficacy and safety outcomes are described within indications.Conclusions This systematic literature review and meta-analysis confirms and updates previous reports on the efficacyand safety of originator filgrastim. Bone pain was thecommonly reported AE associated with filgrastim use.

Keywords Absolute neutrophil count . Granulocytecolony-stimulating factor . Meta-analysis . NEUPOGEN® .

Neutropenia . Systematic review

Introduction

Neutropenia increases risk of bacterial and fungal infections[1–4]. Before the late 1980s, there was no effective primarytreatment for neutropenia; patients were treated with antibiotics,fluid replacement, and general supportive measures [4, 5]. For

Electronic supplementary material The online version of this article(https://doi.org/10.1007/s00520-017-3854-x) contains supplementarymaterial, which is available to authorized users.

* David C. Daledcdale@uw.edu

1 Department ofMedicine, University ofWashington, 1959NE PacificSt, Seattle, WA 98195, USA

2 Duke Cancer Institute, Duke University Medical Center, 30 DukeMedicine Circle, Duke South 25177 Morris Bldg,Durham, NC 27710, USA

3 Clinical Development, Amgen Inc., 1 Amgen Center Drive,Thousand Oaks, CA 91320, USA

4 Global Biostatistical Sciences, Amgen Inc., 1 Amgen Center Drive,Thousand Oaks, CA 91320, USA

5 Pre-Pivotal Drug Product Technologies, Amgen Inc., 1 AmgenCenter Drive, Thousand Oaks, CA 91320, USA

6 Global Scientific Affairs, Amgen Inc., 1 Amgen Center Drive,Thousand Oaks, CA 91320, USA

7 Oxford PharmaGenesis Ltd, Tubney Warren Barn, Tubney,Oxford OX13 5QJ, UK

8 Public Health Sciences Division and Clinical Research Division,Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

Support Care Cancer (2018) 26:7–20DOI 10.1007/s00520-017-3854-x

patients with severe chronic neutropenia (SCN), lack of treat-ment options led to repeated hospitalizations and recurrent andsometimes fatal infections [5, 6]. Cancer patients receiving my-elosuppressive chemotherapy frequently developedchemotherapy-induced neutropenia (CIN), with longer CIN du-ration associated with febrile neutropenia (FN), often necessi-tating dose delays and dose reductions in subsequent chemo-therapy cycles, affecting clinical outcomes [7, 8]. Repeatedbone marrow aspiration was the only available method for he-matopoietic progenitor cell collection.

Granulocyte colony-stimulating factor (G-CSF) stimulatesproliferation and differentiation of neutrophil progenitors andrelease of neutrophils from bone marrow into blood [9, 10].Filgrastim (NEUPOGEN®, Amgen Inc., CA, USA) [11], theoriginator short-acting recombinant human G-CSF, was firstapproved in the US in 1991 and has been used to treat patientsworldwide for over two decades. The pivotal trial leading toapproval showed filgrastim administration decreased FN inci-dence; reduced grade 4 neutropenia incidence, duration, andseverity; and decreased infection rates, duration of antibiotictreatment, and hospitalization in patients with small cell lungcancer (SCLC) receiving myelosuppressive chemotherapy[4]. Similar observations were made in a study of patients withSCN [6].

As of 2016, originator filgrastim has 6 US-approved indi-cations [11]. These include the following: (1) preventing FNin CIN, (2) reducing time to neutrophil recovery and durationof fever in patients with acute myeloid leukemia (AML) re-ceiving induction or consolidation chemotherapy, (3) reducingincidence and duration of sequelae of severe neutropenia inpatients with SCN, (4) mobilizing autologous hematopoieticprogenitor cells in patients undergoing peripheral blood pro-genitor cell (PBPC) collection and therapy, (5) reducing dura-tion of neutropenia and neutropenia-related clinical sequelaein patients with nonmyeloid malignancies undergoingmyeloablative chemotherapy followed by bone marrow trans-plantation (BMT), and (6) increasing survival in patientsacutely exposed to myelosuppressive doses of radiation (he-matopoietic syndrome of acute radiation syndrome [ARS]).

Numerous trials have evaluated efficacy and safety oforiginator filgrastim, which has a long history of use inreal-world settings across diverse indications and popula-tions. However, a systematic review of data from random-ized controlled trials (RCTs), nonrandomized clinical trials(NCTs), and observational studies evaluating use of origi-nator filgrastim in all its US-approved indications has notbeen undertaken.

To date, several biosimilar filgrastims have been ap-proved by European and US regulatory agencies, often onthe basis of clinical safety and efficacy data in one indica-tion. To obtain approval in other indications, biosimilarfilgrastim applicants have relied on extrapolation of datafrom originator filgrastim. A report summarizing the long

history of clinical trial and real-world data for originatorfilgrastim across indications could be useful for the field.

This systematic review and meta-analysis summarizes ef-ficacy, effectiveness, and safety of originator filgrastim instudies comparing filgrastim with placebo or no treatment inany of its US-approved indications. Overall results from theliterature search are presented. Summary data are provided forthe CIN, AML, SCN, and BMT indications. Within each in-dication, data on neutropenia-related complications, overallsurvival (OS), adverse events (AEs), and other relevant out-comes are presented. Meta-analysis results are presented forFN, grade 3 or 4 neutropenia, and bone pain incidence for datafrom RCTs in CIN. Data for all other outcomes are summa-rized descriptively.

Methods

Study design

This study was performed in accordance with the PRISMAguidelines [12], following a prespecified protocol.MEDLINE In-Process & Other Non-Indexed Citations,OVID MEDLINE EMBASE, and Cochrane Library data-bases were searched for English-language publications ofstudies including patients treated with originator filgrastim(NEUPOGEN®) in accordance with US prescribing in-structions [11] (see Online Resource 1). The search cutoffdate was 26 February 2015. No start date was specified aseach database was searched from its start date. Congressabstracts from meetings of 16 relevant organizations (seeOnline Resource 1) published from January 2012 toFebruary 2015 plus abstracts from the 2015 AnnualMeeting of the American Society of Clinical Oncologywere also searched. A hand search of bibliographies wasalso performed for 3 systematic reviews—Cooper et al.[13], Renner et al. [14], and Sheppard et al. [15]—identi-fied as containing relevant information in the initial search.

Study selection

Pre-defined eligibility criteria (Table 1) were used forstudy selection in a two-part process. In part 1, two inde-pendent reviewers screened titles/abstracts and then fulltexts of identified reports for eligibility. In part 2, two in-dependent reviewers assessed titles/abstracts and full textsof publications identified in part 1 to find relevant studiescomparing originator filgrastim to placebo or no treatment.Further excluded at this stage were studies in which < 50patients received filgrastim for all indications except SCN.Due to generally low patient numbers in studies evaluatingfilgrastim in SCN, a protocol amendment was made toallow for inclusion of studies with ≥ 10 patients.

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Table 1 Inclusion and exclusion criteria

Parameter Inclusion criteria Exclusion criteria

Study type: Parts1 and 2

Published English-language studies including:• RCTs• NCTs• Observational studies (longitudinal studies, registry studies,open-label studies)• Systematic reviewsa

Studies in animals but not humansComments, editorials, letters, case reports, guidelines,

health technology assessment reports, economicevaluations, narrative reviews, cancer registry reports,legal cases, debates, newspaper articles, opinions,research protocols, workshops, and patient educationbrochures

Population: Parts1 and 2

Patients receiving filgrastim for one of its 6 US indications listedbelow:• Prophylaxis of CIN• Reducing time to neutrophil recovery and duration of fever inpatients with AML receiving induction or consolidationchemotherapy•Reducing incidence and duration of sequelae of SN in patients withSCN• Mobilizing autologous hematopoietic progenitor cells in patientsundergoing PBPC collection and therapy• Reducing duration of neutropenia and neutropenia-related clinicalsequelae in patients with nonmyeloid malignancies undergoingmyeloablative chemotherapy followed by BMT• Increasing survival in patients acutely exposed tomyelosuppressive doses of radiation (Hematopoietic Syndrome ofARS)

No limits on age, gender, or geographic region

Patients receiving filgrastim outside of its six currentlyapproved US indications

Patients with existing FN receiving G-CSF treatmentStudies in which the tumor type studied, if applicable, was

not clear

Interventions andcomparators:Part 1

Comparative studies of originator filgrastim (NEUPOGEN®) vsplacebo, no treatment, or the following G-CSFs:• Granocyte (lenograstim)• Leridistim• Other short-acting G-CSFs• Neulasta® (pegfilgrastim)• Balugrastim (CG-10639, Neugranin™, albugranin)• Lipegfilgrastim (XM-22, Lonquex®)• Empegfilgrastim (Extimia®, BCD-017, metpegfilgrastim)• LAPS-G-CSF (SPI-2012, HM10460A)• Other long-acting G-CSF

The above interventions (as either primary or secondary prophylaxis)were included

Studies specifying the use of filgrastim but not reportingfilgrastim efficacy or safety data or outcomes of interest

Studies in which filgrastim use was not prophylacticG-CSF-related outcomes not clearStudies in which the short-acting form of G-CSF was not

specified to be filgrastim (NEUPOGEN®)Studies in which data for filgrastim were pooled with data

for other short-acting G-CSFsStudies in which fewer than 50 patients received filgrastim

for all other indications except SCN; in SCN studies with≥ 10 patients were included

Interventions andcomparators:Part 2

Comparative studies of originator filgrastim (NEUPOGEN®) vsplacebo or no treatment

Data for any other short- or long-acting G-CSFs, includingbiosimilar filgrastims

Outcomes: Parts 1and 2

Studies that reported neutropenia, ANC, neutropenia-related infection,or CD34+ cell mobilization and additional outcomes including:• Efficacy (data from RCTs and NCTs) and effectiveness (data fromobservational studies) that reported

- Rate and duration of FN or grade 3 or 4 neutropenia- ANC nadir and white blood cell count- Survival- Rate and duration of hospitalization- Need for antibiotic prophylaxis or treatment- Chemotherapy dose reductions/delays, reduced dose intensity,and number of patients receiving full dose on schedule

- CD34+ cell yield- Number of apheresis sessions required- Time to neutrophil and platelet recovery

• Safety- AEs related to G-CSF, including bone pain, nausea/vomiting,diarrhea, leukocytosis, thrombocytopenia, allergic reactions,splenic rupture, acute respiratory distress syndrome, dyspnea,and alveolar hemorrhage and hemoptysis

Not applicable

a Systematic reviews were used for identification of primary studies but were not included in this review

AE = adverse event; AML = acute amyloid leukemia; ANC = absolute neutrophil count; ARS = acute radiation syndrome; BMT = bone marrowtransplantation; CIN = chemotherapy-induced neutropenia; FN = febrile neutropenia; G-CSF = granulocyte colony-stimulating factor;NCT = nonrandomized clinical trial; PBPC = peripheral blood progenitor cell; RCT = randomized controlled trial; SCN = severe chronic neutropenia;SN = severe neutropenia

Support Care Cancer (2018) 26:7–20 9

Data extraction and analysis

Data on efficacy, effectiveness, and safety were extractedfrom publications identified in part 2. Data were extractedfrom each selected full-text publication, where available;if data were extracted from alternative sources, such ascongress abstract or poster, this was noted. Studies wereclassified according to filgrastim indication [11] and studydesign. Studies were classified into three categories: RCTs(patients randomized to filgrastim or its comparators [pla-cebo or no treatment]); NCTs (patients not randomlyassigned to filgrastim or its comparators); and observa-tional studies (i.e., routine clinical practice under real-world conditions, including longitudinal and registrystudies).

Data collected include study and patient characteristics,efficacy (treatment effect in RCTs and NCTs), effectiveness(treatment effect in observational studies), and safety(Table 1). Data were extracted and reported as presentedby the authors of each publication reviewed. Statistical sig-nificance, where stated, is based on data provided in theoriginal publication, using the standard P < 0.05 boundaryto denote significance. Study quality was assessed and re-ported qualitatively by two independent reviewers; any dis-agreements were resolved by a third reviewer. Reviewersassessed study design on criteria including size of patientpopulation, phase of study, strength of study design, andappropriateness of study design to reach the objective;filgrastim dose, timing, and treatment duration; risk bias;choice of outcome measures; statistical issues; quality ofreporting; quality of the intervention; and generalizabilityof findings.

For safety outcomes, incidence of pre-specified G-CSF-related AEs was collected (Table 1). Additionally, any AEsthat were compared for filgrastim vs no filgrastim in any ofthe studies were collected, as these AEs were presumed tobe filgrastim-related. For each AE, the proportion of pa-tients experiencing the AE overall and, where available,the proportion experiencing events classified as severe orgrade 3/4 were collected.

Statistical analysis

Meta-analysis was performed using the random effectsmodel [16, 17] for FN, grade 3 or 4 neutropenia, and bonepain incidence in CIN to compare results from clinicaltrials (RCTs and NCTs only) for filgrastim vs placebo orno treatment, and relative risks (RRs) were determined.Details for studies included in the meta-analysis are pro-vided in Online Resource 2. Due to limited and heteroge-neous data available for other outcomes and indications,mean or median values were summarized, and no meta-analysis was performed.

Results

Search results

Results of the literature search are summarized in Fig. 1and Online Resource 3. Of 6588 unique records initiallyidentified, 1194 articles were English-language publica-tions reporting RCTs, NCTs, or observational studies thatincluded patients treated with originator filgrastim(NEUPOGEN®) in its 6 US-approved indications andmet eligibility criteria for part 1 of the search. Of these,26 compared filgrastim efficacy, effectiveness, and safetyto placebo or no treatment and met eligibility criteria forpart 2, qualifying for data extraction. These 26 recordswere from 25 separate studies published between 1991[4] and 2013 [18] and represent data from 9018 patients,with filgrastim administered to 4088 patients (Fig. 1,Online Resource 3, and Online Resource 4): 15 were inCIN (11 RCTs, 1 NCT, and 3 observational studies), 6 inAML (5 RCTs and 1 NCT), 2 in SCN (1 RCT and 1observational study), and 2 in BMT (1 RCT and 1 obser-vational study), for a total of 18 RCTs, 2 NCTs, and 5observational studies. No studies evaluating filgrastimcompared with placebo or no treatment in the PBPC orARS indications met eligibility criteria for data extraction.Data on filgrastim dose, timing, and duration were pro-vided in most studies and varied across studies, evenwithin indication (Online Resource 4 and OnlineResource 5).

Outcomes for filgrastim vs placebo or no treatmentby indication

CIN

The 15 studies evaluating filgrastim vs placebo or no treat-ment in CIN enrolled 6521 patients in total, with filgrastimadministered to 2691 patients (Online Resource 4 andOnline Resource 6). Eleven studies were RCTs (10 full ar-ticles and 1 [19] abstract). Six RCTs were in solid tumors(breast cancer [20–22], SCLC [4, 23], and germ cell tumors[24]), 3 were in non-Hodgkin’s lymphoma (NHL) [25–27],and 2 were in acute lymphoblastic leukemia (ALL) [28, 29].One study [30] was an NCT in non-small cell lung cancer(NSCLC) and NHL. The remaining 3 [18, 31, 32] wereobservational studies conducted in mixed tumor types.

Several studies reported data on FN, grade 3 or 4 neutro-penia, and bone pain incidence for filgrastim vs placebo orno treatment in CIN (Online Resource 6), and RRs for theseoutcomes were determined by meta-analysis (Fig. 2 andFig. 3). Limited data were reported for the remaining out-comes; therefore, data for these additional outcomes weresummarized descriptively.

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FN incidenceNine of the 11 RCTs in CIN [4, 19–21, 23, 24,26, 27, 29] reported FN incidence (Online Resource 6) andwere included in the meta-analysis (Fig. 2a). Data analyzedwere from 2197 total patients (filgrastim, n = 1130; placeboor no treatment, n = 1067). The risk of developing FN wasmuch lower with filgrastim vs placebo or no treatment (RR0.63, 95% CI 0.53–0.75). In addition, 3 observational studies[18, 31, 32] reported FN incidence, and statistical compari-sons were provided in all 3 studies. Two [18, 32] reportedsignificant reductions in FN risk with filgrastim; the other[31] reported no difference in FN risk for filgrastim vs place-bo or no treatment.

Grade 3 or 4 neutropenia incidence Five RCTs [4, 19, 20,25, 27] and 1 NCT [30] reported grade 3 or 4 neutropeniaincidence (Table 2 and Online Resource 6) and were includedin the meta-analysis (Fig. 2b). Data analyzed were from 1409total patients (filgrastim, n = 714; placebo or no treatment,n = 695). The risk of developing grade 3 or 4 neutropeniawas significantly lower with filgrastim vs placebo or nofilgrastim (RR 0.50, 95% CI 0.37–0.68).

Duration of grade 3 or 4 neutropenia Four RCTs [4, 21, 23,28] and 1NCT [30] reported duration of grade 3 or 4 neutropenia(Table 3 and Online Resource 6), with statistical comparisons

Fig. 1 PRISMA flow diagram.AML = acute myeloid leukemia;ARS = acute radiation syndrome;BMT = bone marrowtransplantation;CIN = chemotherapy-inducedneutropenia; G-CSF = granulocyte colony-stimulating factor;NCT = nonrandomized clinicaltrial; PBPC = peripheral bloodprogenitor cell;RCT = randomized controlledtrial; SCN = severe chronicneutropenia

Support Care Cancer (2018) 26:7–20 11

provided in 2 RCTs [4, 28]. In both studies, median duration ofgrade 3 or 4 neutropenia was significantly shorter with filgrastimvs placebo [4, 28]. Duration of grade 3 or 4 neutropenia wasnumerically lower with filgrastim in the other 2 RCTs [21, 23]and the 1 NCT [30].

Infection rates Seven RCTs [4, 23–26, 28, 29] and 1 obser-vational study [31] reported infection rates, with statistical

comparisons provided in 5 RCTs [23, 25, 26, 28, 29] andthe observational study [31]. Three RCTs reported signifi-cantly lower overall infection rates with filgrastim vs placebo[25, 26, 29], whereas 2 [23, 28] reported nonsignificantlylower infection rates with filgrastim. Infection incidencewas numerically lower with filgrastim in 1 of the remainingRCTs [4], but not different in the other RCT [24]. The obser-vational study [31] reported no significant difference in

Fig. 2 Risk estimates in CIN for (a) FN incidence (2197 total patients;filgrastim, n = 1130; placebo or no treatment, n = 1067) and (b) grade 3 or4 neutropenia incidence (1409 total patients; filgrastim, n = 714; placebo orno treatment, n = 695). Random effects meta-analysis was performed for theoutcomes to compare data from clinical trials for filgrastim vs placebo or notreatment and relative risk determined. Note: filgrastim = originator filgrastim(NEUPOGEN®). aData for patients who receivedCHOP (filgrastim, n = 101;no filgrastim, n= 104) and thosewho receivedCNOP (filgrastim, n= 103; no

filgrastim, n = 100) in the Osby et al. [27] study were analyzed separately.bData for patients with NSCLC (filgrastim, n = 24; no filgrastim, n = 9) andthose with NHL (filgrastim, n = 10; no filgrastim, n = 5) in the Blayney et al.[30] study were analyzed separately. Chemotherapy regimens:CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone;CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone.CIN = chemotherapy-induced neutropenia; FN = febrile neutropenia;NSCLC = non-small cell lung cancer; NHL = non-Hodgkin’s lymphoma

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infection rates with filgrastim primary prophylaxis vs nofilgrastim primary prophylaxis.

Antibiotic use Five RCTs [4, 23, 25, 26, 29] reported antibi-otic use, with statistical comparisons provided in 2 [23, 26].One [23] reported significantly lower incidence of antibioticuse with filgrastim vs placebo or no filgrastim; the other re-ported significantly reduced days of antibiotic use withfilgrastim vs placebo or no filgrastim [26]. Although statisticalsignificance was not reported in the remaining 3 studies, daysof antibiotic use were numerically less with filgrastim in onestudy [4], fewer patients required parenteral antibiotics in an-other study [25], and fewer patients received intravenous (IV)antibiotics and median days of antibiotic use were less in theother study [29].

Hospitalizations Six RCTs [4, 23, 26–29], 1 NCT [30], and 1observational study [31] reported hospitalizations, with statis-tical comparisons provided in 6 RCTs and the observationalstudy [31]. Four RCTs [23, 27–29] demonstrated significantlyimproved hospital outcomes with filgrastim vs placebo or nofilgrastim. Significant improvements were observed ininfection-related hospitalization in 1 study [23],granulocytopenic fever requiring hospitalization in 1 study[27], and median days of hospitalization in 2 studies [28,29]; however, hospitalization rates were not significantly dif-ferent between filgrastim and no filgrastim in one of the stud-ies [29]. For the 2 remaining RCTs, days of hospitalizationwere numerically lower with filgrastim in one study [4] andnot significantly different in the other [26]. In the NCT [30],

mean days of hospitalization were numerically lower withfilgrastim in NSCLC but were numerically higher in NHL.The observational study [31] reported no significant differ-ence in hospitalization rates with filgrastim primary prophy-laxis vs no filgrastim primary prophylaxis.

Chemotherapy relative dose intensity (RDI), dose reduc-tions, and/or delays Six RCTs [20, 23–27] and 1 observa-tional study [18] reported on chemotherapy dosing. FiveRCTs [20, 24–27] reported RDI, with statistical compari-sons provided in all 5 studies. RDI was significantly im-proved with filgrastim vs no filgrastim in germ cell tumor[24] and NHL [27], and was improved, but not significant-ly different, in breast cancer [20] and NHL [25, 26]. In theobservational study [18], RDI was significantly higherwith filgrastim vs no filgrastim in the subset of patientswho received fluorouracil, epirubicin, cyclophosphamide,and docetaxel (FEC/D), and the proportions of patientswho achieved RDI > 85% in this population was numeri-cally higher, but not significantly different, with filgrastimvs no filgrastim. Two RCTs [20, 23], 1 NCT [30], and 1observational study [18] reported chemotherapy dose de-lays and dose reductions, with statistical comparisons pro-vided in 2 RCTs and 1 observational study. In the RCTs,dose reduction was significantly reduced with filgrastim vsplacebo or no filgrastim in SCLC [23] and breast cancer[20]. Dose delay was significantly reduced in breast cancer[20] and numerically reduced in SCLC [23], although thestatistical significance of this difference was not reported.In the observational study, both dose delays and dose

Fig. 3 Risk estimates for bone pain incidence in CIN (1078 total patients;filgrastim, n = 540; placebo or no treatment, n = 538). Random effectsmeta-analysis was performed and relative risk determined. Note:filgrastim = originator filgrastim (NEUPOGEN®). Studies with missingreports of events for the placebo or no treatment arm (therefore, eventsnot assumed to be 0) were not included in the analysis. aReported 0events in the placebo or no treatment arm; 0.5 events added to each arm

for an adjusted event rate. bData for patients who received CHOP(filgrastim, n = 101; no filgrastim, n = 104) and those who receivedCNOP (filgrastim, n = 103; no filgrastim, n = 100) in the Osby et al. [27]study were analyzed separately. Chemotherapy regimens:CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone;CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone.CIN = chemotherapy-induced neutropenia

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reductions were reduced with filgrastim vs no filgrastim,but differences did not reach statistical significance [18]. Inthe NCT [30], filgrastim numerically reduced both dosedelays and dose reductions in NSCLC and also reduceddose delays in NHL. Of interest, dose reductions werehigher with filgrastim vs no filgrastim in NHL [30] (12vs 0%).

OS OS was reported in 8 RCTs [4, 20, 23, 25–29]. Reportedmedian follow-up times were 30months [25], 33 months [26],55 months [20], 57 months [27], and 4.7 years [28]. Event-free survival at 3 years was reported to be 83% in bothfilgrastim and placebo arms in one study [29]; whereasfollow-up times were not specified in the remaining 2 studies[4, 23]. No statistical comparisons were shown, and none ofthe studies reported a difference in survival for filgrastim vsplacebo or no filgrastim.

AEs Five of 11 RCTs [4, 23, 25, 27, 28] reported sufficienthomogeneous data on bone pain incidence to allow for meta-

analysis (Fig. 3). Data analyzed were from 1078 total patients(filgrastim, n = 540; placebo or no treatment, n = 538). Therisk of developing bone pain was higher with filgrastim vsplacebo or no treatment (RR 2.61, 95% CI 1.29–5.27). Fiveadditional studies [4, 20, 21, 23, 26] reported data on bonepain and/or musculoskeletal pain, with overall rates reportedranging from < 1.0 to 42.5%. Other AEs reported in CINinclude hematological, gastrointestinal, and general toxicities,most likely related to chemotherapy (Online Resource 6).Incidences of other nonhematological AEs were similar orlower with filgrastim vs placebo or no treatment, except intwo instances. The first exception was grade 1/2 pulmonarytoxicity reported in 1 RCT [24]. Higher proportions of pa-tients administered filgrastim vs no filgrastim experiencedgrade 1/2 pulmonary toxicity after receiving cisplatin,etoposide, bleomycin/etoposide, bleomycin (BEP/EP) (25 vs16%) or bleomycin, vincristine, cisplatin/cisplatin,ifosfamide, etoposide, bleomycin (BOP/VIP-B) (17 vs14%). However, no differences were observed in the propor-tions of patients who experienced grade 3 or grade 4

Table 2 Incidence of grade 3 or 4 neutropenia in CIN

Author Disease type Filgrastim interventionand patient numbers

Incidence of grade 3 or 4 neutropenia P value

Randomized controlled trials

Crawford et al. [4] SCLC N = 199Filgrastim = 95Placebo = 104

Grade 4 neutropenia in cycle 1: 84 vs 98% P = 0.001

Papaldo et al. [20] Breast cancer N = 503Filgrastim = 254No filgrastim = 249

Grade 3/4 neutropenia: 28.6 vs 81.6% P < 0.00001

He et al. [19] Breast cancer N = 107PP filgrastim = 53No PP filgrastim = 54

Grade 3/4 neutropenia: 12.2 vs 52.3% P < 0.001

Zinzani et al. [25] High-grade NHL N = 149Filgrastim = 77No filgrastim = 72

Grade 4 neutropenia: 23.0 vs 55.5% P = 0.00005

Osby et al. [27] NHL N = 455Filgrastim = 226No filgrastim = 229

Granulocytopenia (< 0.5 × 109/L):CHOP arms55 vs 89%CNOP arms64 vs 86%

Not reported

Nonrandomized clinical trial

Blayney et al. [30] NSCLC and NHL NSCLC (n = 33):a

Filgrastim = 24No filgrastim = 9

NHL (n = 15):b

Filgrastim = 10No filgrastim = 5

Grade 3 and grade 4 neutropenia: 62 and 77% lowerwith filgrastim compared to control arm

Not reported

Note: filgrastim = originator filgrastim (NEUPOGEN® )aData reported are for the subgroup of 33 patients with NSCLC who received the standard 21-day chemotherapy regimenbData reported are for the subgroup of 15 patients with NHL who received the standard 21-day chemotherapy regimen

Chemotherapy regimens: CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CNOP = cyclophosphamide, mitoxantrone, vincristine,prednisone

CIN = chemotherapy-induced neutropenia; NHL = non-Hodgkin’s lymphoma; NSCLC = non-small cell lung cancer; PP = primary prophylaxis;SCLC = small cell lung cancer

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pulmonary toxicity with or without filgrastim. The other ex-ception was significantly increased grade 3/4/5 pain withfilgrastim vs placebo (21 vs 14%, P = 0.026) in ALL patients[28]. The 2 RCTs in ALL identified in this search did notreport differences in subsequent development of AML forfilgrastim vs placebo, with a follow-up of 3 years in one study[29] and 4.7 years in the other [28].

AML

The 6 studies evaluating filgrastim vs placebo or no treatmentin AML enrolled 1554 patients in total, with 769 receivingfilgrastim (Online Resources 4 and 7). One RCT [33] reportedthe effect of filgrastim on outcomes following both inductionand consolidation chemotherapy, 3 RCTs [34–36] reported theeffect of filgrastim following induction chemotherapy, and 1RCT [37] and 1 NCT [38] reported the effect of filgrastimfollowing consolidation chemotherapy.

Absolute neutrophil count (ANC) recovery Three RCTs[33, 35, 36] reported time to ANC recovery following induc-tion chemotherapy, with statistical comparisons provided in 2studies [33, 36]. Both reported significantly shorter times toANC recovery with filgrastim vs no filgrastim [33, 36]. In theremaining RCT [35], time to ANC recovery was also numer-ically shorter with filgrastim. Time to ANC recovery follow-ing consolidation chemotherapy was reported in the 1 NCT[38] and was significantly shorter with filgrastim vs nofilgrastim.

Infection rates Three RCTs [33, 35, 36] reported infectionrates following induction chemotherapy, with statistical com-parisons provided in all 3. Overall, infection rates were notsignificantly different for filgrastim vs no filgrastim. Infectionrates for filgrastim vs no filgrastim following consolidationchemotherapy were reported in 1 RCT [37] and 1 NCT [38],with statistical comparisons provided in the RCT. No

Table 3 Duration of grade 3 or 4 neutropenia in CIN

Author Disease type Filgrastim interventionand patient numbers

Median duration of grade 3or 4 neutropenia

P value Mean durationof severeneutropenia

Pvalue

Randomized controlled trials

Crawford et al.[4]

SCLC N = 199Filgrastim = 95Placebo = 104

Grade 4 neutropenia in cycle 1 (days):3 vs 6

P < 0.001

Grade 4 neutropenia over 6 cycles (days):1 vs 6

P < 0.001

Trillet-Lenoiret al. [23]

SCLC N = 129Filgrastim = 65Placebo = 64

Neutropenia (ANC < 1 × 109/L)over 6 cycles (days):

6 vs 15Del Giglio et al.[21]

Breast cancer N = 348Filgrastim = 136XM02 = 140Placebo/XM02 = 72

Severe neutropenia(days):

cycle 11.1 vs 1.1 vs 3.8cycle 40.7 vs 0.7 vs 0.6

NR

Larson et al. [28] ALL N = 198Filgrastim = 102Placebo = 96

Median (IQR)Neutropenia (ANC < 1000/μL) (days):Course I13 (10–16) vs 20 (15–27)

P < 0.001

Course IIA5 (0–12) vs 13 (6–18)

P < 0.001

Course IIB11 (4–17) vs 14 (10–25)

P = 0.001

Nonrandomized clinical trial

Blayney et al.[30]

NSCLC andNHL

NSCLC (n = 33):a

Filgrastim = 24No filgrastim = 9

NHL (n = 15):b

Filgrastim = 10No filgrastim = 5

Median duration of grade 3 and grade 4neutropenia: 81 and 94% lower comparedto control arm

Note: filgrastim = originator filgrastim (NEUPOGEN® )aData reported are for the subgroup of 33 patients with NSCLC who received the standard 21-day chemotherapy regimenbData reported are for the subgroup of 15 patients with NHL who received the standard 21-day chemotherapy regimen

ALL = acute lymphoblastic leukemia; ANC = absolute neutrophil count; CIN = chemotherapy-induced neutropenia; IQR = interquartile range;NHL = non-Hodgkin’s lymphoma; NR = not reported; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer

Support Care Cancer (2018) 26:7–20 15

significant differences were seen in the RCT [37], and nonumerical differences were seen in the NCT [38].

Antibiotic use Four RCTs [33–36] reported antibiotic useduring the induction phase, and statistical comparisons areprovided in all 4. All 4 reported no significant differencesbetween treatment groups. Antibiotic use during the consoli-dation phase was reported in 1 RCT [37], with the studyreporting significantly less antibiotic use with filgrastim inboth consolidation cycles.

Hospitalizations Three RCTs [33–35] reported hospitaliza-tion outcomes during the induction phase, with statisticalcomparisons provided in 2 RCTs [33, 34]. Duration of hospi-talization was significantly shorter with filgrastim vs nofilgrastim in 1 RCT [33] and nonsignificantly shorter in theother RCT [34]. Duration of hospitalization was not numeri-cally different in the other RCT [35]. Two RCTs [33, 37] and 1NCT [38] reported hospitalization outcomes during the con-solidation phase, with statistical comparisons provided in all 3studies. Duration of hospitalization was significantly shorterwith filgrastim vs no filgrastim for the cumulative inductionand consolidation phases in 1 RCT [33] and the consolidationphase in the other RCT [37]. In the NCT [38], incidence ofhospitalization was significantly lower and duration of hospi-talization was numerically lower with filgrastim vs nofilgrastim.

OS OS was reported in 4 RCTs in which patients receivedinduction chemotherapy [33–36], with statistical comparisonsprovided in 3 RCTs [33–35]. No significant difference in OSwas observed for filgrastim vs no filgrastim in the 3 RCTs.Similarly, the other RCT did not show a numerical differencein OSwith filgrastim use [36].Median follow-up times rangedfrom 20 months [36] to 7 years [33]. OS was reported in 1RCT [37] and 1 NCT [38] in which patients received consol-idation chemotherapy. In the RCT [37], 2-year OS (standarddeviation) was 64% (6%) vs 63% (6%) for filgrastim vs nofilgrastim. In the NCT [38], median survival of patients whoreceived the third intensification chemotherapy course was3.4 years for filgrastim vs 2.4 years for no filgrastim. Long-term follow-up in the study in which patients received bothinduction and consolidation chemotherapy [33], reported as aseparate study [39], confirmed no detrimental effect offilgrastim use on OS in patients with AML at a medianfollow-up of 7 years.

AEsAmongAEs reported, incidence of bone pain and/or mus-culoskeletal pain for filgrastim vs no filgrastim was reported in2 studies: 1 vs 5% [35] and 2 vs 1% [33]. Musculoskeletal painwas also mentioned, but incidence not provided, in 1 RCT[34], and 3 patients were reported to experience mildfilgrastim-related musculoskeletal pain in another RCT [36].

SCN

One RCT [6] and 1 observational study [40] met eligibilitycriteria for data extraction in SCN (Online Resource 8). Thetwo studies enrolled 162 patients in total, with 79 receivingfilgrastim.

The pivotal RCT leading to filgrastim approval in the US[6] reported a significant increase in median ANC in patientswho received filgrastim vs those who were observed for4 months with no filgrastim (N = 123). There were also sig-nificantly fewer infections (~50% reduction) and less IVanti-biotic use (~70% reduction) with filgrastim. Overall, medianincidence and median duration of hospitalization were low.Exposure-adjusted AEs (total number of events divided bytotal study exposure in patient months) in patients after receiv-ing filgrastim vs before receiving filgrastim were as follows:headache, 35 vs 24%; general musculoskeletal pain, 25 vs10%; transient bone pain, 17 vs 6%; and rash, 10 vs 4% [6].Asymptomatic palpable splenomegaly was reported in 18/123patients (14%) before filgrastim and 29/120 patients (24%)who received filgrastim.

The observational study [40] compared 16 pediatric pa-tients with chronic neutropenia who received filgrastim with23 who did not receive filgrastim. Groups were heteroge-neous, and criteria for filgrastim administration were not spec-ified. In the no filgrastim group, 16 of 23 patients recoveredspontaneously, whereas 11 of 16 patients in the filgrastimgroup remained on filgrastim throughout the study period.For patients with idiopathic severe neutropenia, the largestgroup (n = 31), those selected for treatment with filgrastimhad histories of significantly more infections and hospitaliza-tions than those not treated with filgrastim. With filgrastimtreatment, rate of infections in the treatment group decreasedto that of the comparison group, suggesting a benefit offilgrastim treatment. Of note, the schedule of filgrastim ad-ministration in this observation study [40] was different fromthe RCT [6] (Online Resource 4), and timing of blood countobservations was not specified.

BMT

One RCT [41] and 1 observational study [42] that assessedfilgrastim’s effect on hematopoietic recovery followinghigh-dose chemotherapy with PBPC support met eligibilitycriteria for data extraction (Online Resource 9). The 2 stud-ies enrolled 781 patients in total, with 549 patients receiv-ing filgrastim.

In the RCT in ALL or solid tumors (filgrastim, n = 51; nofilgrastim, n = 66) [41], median (range) time to achieve ANC> 0.5 × 109/L was 10 (7–14) days with filgrastim and 11 (8–21) days with no filgrastim (P < 0.009). Median time (range)to platelet engraftment was 15 (9–100) days with filgrastimand 14 (11–71) days with no filgrastim (P < 0.005). Duration

16 Support Care Cancer (2018) 26:7–20

of antibiotic use and hospitalization were not significantlydifferent between treatment arms [41].

The single-institution observational study [42] analyzedpatients who underwent autologous transplant for multiplemyeloma with or without filgrastim (filgrastim, n = 498; nofilgrastim, n = 166), starting on day 6 after transplantation.Median time to ANC recovery was 12.5 days with filgrastimand 13.5 days with no filgrastim (P < 0.001). Median time toplatelet engraftment was 14.5 days in both groups. Incidenceof bacteremia was significantly higher with filgrastim, inci-dence and duration of hospitalization were significantly higherwith filgrastim, and all-cause mortality was similar betweentreatment groups.

Discussion

This systematic review examined medical literature on origi-nator filgrastim in all its US-approved indications based onpre-specified criteria and identified 1194 unique reports pub-lished in a period spanning > 29 years (1987–2015). This isthe first study to systematically review and perform a meta-analysis of the efficacy, effectiveness, and safety of filgrastimin clinical trials and real-world settings. The 18 RCTs, 2NCTs, and 5 observational studies in CIN, AML, SCN, andBMT identified in this search span from 1991 [4] to 2013 [18];21/25 studies (84%) were published between 1991 and 2010.The 2 registration studies for the BMT indication did not meetthe inclusion criteria for the present analysis as they enrolled< 50 patients in the filgrastim arm [43, 44]. No studies evalu-ating filgrastim vs placebo or no treatment in PBPC met theinclusion criteria for the present analysis. Similarly, no eligiblestudies that evaluated filgrastim in patients with ARS wereidentified in this search. Filgrastim’s approval for ARS wasbased on efficacy studies in animals and filgrastim data fromother approved indications [11].

Filgrastim dose, timing, and duration were provided inmost studies in CIN [4, 19–21, 23–31], AML [33–38], SCN[6, 40], and BMT [41, 42] but varied across studies (OnlineResources 4 and 5). Further evaluation is needed to under-stand effects of modifications on dose, timing, and durationof filgrastim in different indications.

Overall, the common filgrastim benefit across indicationswas decreasing incidence and/or duration of severe neutrope-nia, assessed as the outcomes of FN or fever incidence and/orduration, grade 3 or grade 4 neutropenia incidence and/orduration, and time to ANC recovery. All 25 studies reportedat least one of these outcomes, and 21 (84%) provided statis-tical comparisons for filgrastim vs placebo or no treatment inat least one of the outcomes (11 of 15 CIN studies, all AMLstudies, all SCN studies, and all BMT studies) (OnlineResources 6, 7, 8, 9). Sixteen of 21 studies (76%) demonstrat-ed significant improvement with filgrastim in at least one of

the outcomes (9 of 15 CIN studies, 4 of 6 AML studies, 1 of 2SCN studies, and all BMTstudies). The observational study inSCN by Yilmaz et al. [40] showed a nonsignificant reductionin median duration of neutropenia that resolved.

CINwas the indicationwith the most evidence of improvedefficacy with filgrastim vs placebo or no treatment. Meta-analysis of data from 9 RCTs [4, 19–21, 23, 24, 26, 27, 29]with 2197 patients in total (filgrastim, n = 1130; placebo or notreatment, n = 1067) demonstrated decreased FN incidencewith filgrastim (RR 0.63, 95% CI 0.53–0.75), with data fromthe additional 2 observational studies [18, 32] also showingsignificantly decreased FN incidence with filgrastim. Meta-analysis of data from 5 RCTs and 1 NCT with 1409 patientsin total (filgrastim, n = 714; placebo or no treatment, n = 695)demonstrated decreased grade 3 or 4 neutropenia incidencewith filgrastim (RR 0.50, 95% CI 0.37–0.68).

A recent retrospective study suggested that OS might begreater among patients receiving filgrastim vs placebo [45],but differences were not statistically significant. In our analy-sis, none of the evaluated studies reported a difference in OSfor filgrastim vs placebo or no treatment, suggesting thatfilgrastim does not appear to have a detrimental effect onlong-term outcomes in oncology patients. Cancer treatmentis complex; though FN and infection are critical, they arenot the only factors determining patient outcomes. Of note,follow-up times were not consistently reported across theevaluated studies.

Chemotherapy dosing outcomes were mostly reported inCIN, with improvements observed with filgrastim use.Significant improvements in RDI were reported in germ celltumor [24] and NHL [27], significantly fewer dose reductionsin SCLC [23] and breast cancer [20], and significantly fewerdose delays in breast cancer [20]. These reports are consistentwith recent reports of G-CSF use to maintain planned RDI ofchemotherapy in various tumor types [46–49].

In AML, filgrastim shortened time to ANC recovery duringinduction chemotherapy in 3 RCTs [33, 35, 36] and duringconsolidation therapy in 1 NCT [38], but no correspondingimprovements in infection rates were observed. A possibleexplanation is that the myeloablative nature of chemotherapyused for acute leukemias results in a period of neutropeniawith high infection rates that may not be impacted byfilgrastim.

In a pivotal SCN RCT, filgrastim reduced the severity andduration of neutropenia with > 16-fold increase in ANC com-pared to the control [6]. The study also showed a significantincrease in marrow neutrophils and a significant reduction ininfection-related events and antibiotic use with filgrastim [6].Long-term follow-up of this population and nearly 800 otherpatients affirmed these benefits [50]. As noted earlier, in theobservational study by Yilmaz et al. [40] in which the moreseverely ill patients were treated with filgrastim, ANC wasreported to increase with only one patient responding poorly.

Support Care Cancer (2018) 26:7–20 17

Other outcomes such as infections and hospitalizations couldnot be meaningfully evaluated because of the nature of thestudy.

In patients undergoing hematopoietic recovery followinghigh-dose chemotherapy with PBPC support, median time toANC recovery was shorter with filgrastim vs no filgrastim inthe RCT (10 vs 11 days, P < 0.009) [41] and the observationalstudy (12.5 vs 13.5 days, P < 0.001) [42]. Filgrastim did notreduce time to platelet engraftment in either study. Also,filgrastim did not improve other outcomes such as incidenceof infection [42], duration of antibiotic use [41], incidence orduration of hospitalization [41, 42], or all-cause mortality[42]. For the observational study [42], incidence of infectionand incidence and duration of hospitalization were higher withfilgrastim. Of note, the cases reported in this observationalstudy [42] ranged from March 2008 to December 2009.Lack of improvement in patient outcomes might be partiallyexplained by the overall improvement in stem cell transplan-tation in the past decade [51].

The most commonly reported filgrastim-related AE wasbone pain. In the meta-analysis of data from 5 RCTs in CIN[4, 23, 25, 27, 28] with 1078 patients (filgrastim, n = 540; nofilgrastim, n = 538), risk of bone pain was higher withfilgrastim (RR 2.61, 95% CI 1.29–5.27). In the remainingCIN studies [4, 20, 21, 23, 26], bone pain rates ranged from< 1.0 to 42.5%. Increased bone pain with filgrastim vs pla-cebo or no treatment was also reported in SCN (generalmusculoskeletal pain, 25 vs 10%; transient bone pain, 17vs 6% [6]).

Other salient AEs include pulmonary toxicity in patientswith germ cell tumors [24] and splenomegaly in patients withSCN [6]. In Fossa et al. [24], higher proportions of patientsreceiving filgrastim vs not receiving filgrastim experiencedgrade 1/2 pulmonary toxicity after BEP/EP (25 vs 16%) orBOP/VIP-B (17 vs 14%) chemotherapy; however, these dif-ferences were not observed in the proportions of patients whoexperienced grade 3 or 4 pulmonary toxicity. Overall, chemo-therapy dose intensities were similar across arms in that study[24]. Dale et al. [6] reported asymptomatic palpable spleno-megaly in 29 of 120 patients (24%) after receiving filgrastimvs 18 of 123 patients (14%) before receiving filgrastim.

Several limitations should be noted. Firstly, definitionsof efficacy outcomes, baseline characteristics and diseasehistory, dose and timing of filgrastim, and the power todetect significant differences in evaluated outcomes variedamong studies. Secondly, data from observational studiesare likely to be subject to confounding by indication.Lastly, pre-determined inclusion criteria excluded pivotalBMT and PBPC studies due to sample size. However, theadvantage of the current systematic review and meta-analysis is that it allowed a comparison of outcomes withfilgrastim vs placebo or no treatment in the absence of datafrom recent clinical trials.

In conclusion, a large dataset evaluating originatorfilgrastim in US-approved indications exists in the literature.Findings from this study confirmed previous reports on theefficacy and effectiveness of filgrastim, with the most evi-dence demonstrated in decreased FN and grade 3 or 4 neutro-penia incidence in CIN, with a similar trend of improvementin other outcomes in CIN and in other indications. Bone painwas the most commonly reported AE associated withfilgrastim use across studies and indications.

Acknowledgments This study was supported by Amgen Inc. MarthaMutomba (on behalf of Amgen Inc.) and Kerri Hebard-Massey (fromAmgen Inc.) provided writing assistance.

Funding This study was supported by Amgen Inc.

Compliance with ethical standards

Disclosure of potential conflict of interest David Dale has receivedresearch support from and is a consultant for Amgen Inc. JeffreyCrawford has received research support from Amgen Inc., AstraZeneca,Bayer, Clovis, andGTx; has been a scientific advisor forMerck, Novartis,and Pfizer; and has participated as a member of a data and safety moni-toring board for Celgene, G1 Therapeutics, Janssen, Merrimack, andRoche. Zandra Klippel, Maureen Reiner, Timothy Osslund, Ellen Fan,and Phuong Khanh Morrow are employees of and own stock in AmgenInc. Kim Allcott is an employee of Oxford PharmaGenesis Ltd., whichhas received project funding from Amgen Inc. and Amgen (Europe)GmbH. Gary Lyman has received research support from Amgen Inc.

Research involving human participants and/or animals This articledoes not contain any studies with human participants or animals per-formed by any of the authors.

Informed consent Formal consent was not required, as the article doesnot contain any studies involving human participants performed by any ofthe authors.

Open Access This article is distributed under the terms of the CreativeCommons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits anynoncommercial use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and thesource, provide a link to the Creative Commons license, and indicate ifchanges were made.

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